Discovery of ((4R,5S)-5-amino-4-(2,4,5- trifluorophenyl)cyclohex-1-enyl)-(3- (trifluoromethyl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (ABT-341), a highly potent, selective, orally efficacious, and safe dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes |
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| Authors: | Pei Zhonghua Li Xiaofeng von Geldern Thomas W Madar David J Longenecker Kenton Yong Hong Lubben Thomas H Stewart Kent D Zinker Bradley A Backes Bradley J Judd Andrew S Mulhern Mathew Ballaron Stephen J Stashko Michael A Mika Amanda K Beno David W A Reinhart Glenn A Fryer Ryan M Preusser Lee C Kempf-Grote Anita J Sham Hing L Trevillyan James M |
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| Affiliation: | Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6098, USA. zhonghua.pei@abbott.com |
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| Abstract: | Dipeptidyl peptidase IV (DPP4) deactivates glucose-regulating hormones such as GLP-1 and GIP, thus, DPP4 inhibition has become a useful therapy for type 2 diabetes. Optimization of the high-throughput screening lead 6 led to the discovery of 25 (ABT-341), a highly potent, selective, and orally bioavailable DPP4 inhibitor. When dosed orally, 25 dose-dependently reduced glucose excursion in ZDF rats. Amide 25 is safe in a battery of in vitro and in vivo tests and may represent a new therapeutic agent for the treatment of type 2 diabetes. |
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